Summary: New research has uncovered a genetic connection between autism spectrum disorder ( ASD ) and myotonic dystrophy type 1 ( DM1 ), a rare neuromuscular disease. The study identifies tandem repeat expansions ( TREs ) in the DMPK gene as a shared mechanism that disrupts gene splicing and contributes to ASD-like social behaviors in individuals with DM1.
This mis-splicing creates proteins disparities that interfere with mental development and function. The studies provide new insights into autism’s biological processes and may inform future detail treatments aimed at restoring protein work.
Important Information:
- Shared Genetic Mechanism: Las in the DMPK protein website DM1 and ASD by disrupting protein cutting essential for brain development.
- Increased Risk: Citizens with DM1 are 14 times more likely to produce dementia compared to the general population.
- Possible Therapies: Research is underway to investigate treatments that may release protein absorbed by harmful RNA caused by TREs.
Origin: Hospital for Sick Kids
Scientists from The Hospital for Sick Children ( SickKids ) and University of Las Vegas Nevada ( UNLV ) have uncovered a genetic link between autism spectrum disorder ( ASD ) and a rare genetic condition called myotonic dystrophy type 1 ( DM1 ).
The study, published today in Nature Science, suggests that while ASD has recently been characterized by a reduction of protein work, another method may be leading to the cultural behaviours frequently observed in individuals with ASD.
DM1 is an inherited condition which causes liberal tissue damage and weakness. While ASD is present in around one per cent of the common community, it is 14 times more likely to develop in individuals with DM1.
The study revealed that the genetic variation that causes DM1 — tandem repeat expansions ( TREs ) in the DMPK gene — also impacts brain development. The research group found that the effects of TREs interfere with a critical operation called gene cutting, which is necessary for protein work.
The disturbance causes a proteins imbalance that can result in mis-splicing of many genes involved in mental performance, and may explain why some of the interpersonal and psychological effects of ASD develop in individuals with DM1.
“Our results represent a new way to describe the biological development of dementia, ” explains Dr. Ryan Yuen, Senior Scientist in the Genetics & Genome Biology program at SickKids.
“By identifying the chemical road behind this relationship, we may begin to research new approaches to ASD treatment and the development of perfection therapies that release these proteins back into the genome. ”
TREs occur when sections of a DNA strand are repeated two or more times, and the likelihood of those repeats causing errors in gene function increases each time.
In 2020 Yuen discovered that TREs are genetic contributors to autism, identifying more than 2,588 different places in the genome where TREs were much more prevalent in people with ASD. Similarly, people with DM1 have a TRE in the DMPK gene.
“A variation really stood out to me that we see in rare neuromuscular disease, ” says Dr. Łukasz Sznajder, a research lead and Assistant Professor at UNLV.
“This is how we started connecting the dots. We found a molecular link, or overlap, which we believe is the core of causing autistic symptoms in children with myotonic dystrophy. ”
As the tandem repeat expands in the DMPK gene, the research team, including collaborators at the University of Florida and Adam Mickiewicz University ( Poland ), found its altered RNA binds to a protein that is involved in gene splicing regulation during brain development.
This so-called “toxic RNA” depletes the protein and prevents it from binding to other RNA molecules in important areas of the genome, causing a protein imbalance which results in mis-splicing other genes.
“TREs are like a sponge that absorbs all these important proteins from the genome. Without this protein, other areas of the genome don’t function properly, ” explains Yuen.
The Yuen Lab and Sznajder Lab are already exploring whether this mis-splicing is happening in other genes associated with ASD, as well as how their findings could inform precision therapies that release these proteins back into the genome.
Some of this work is already underway. In 2020, Dr. Christopher Pearson, Senior Scientist in the Genetics & Genome Biology program at SickKids, identified a molecule that can contract TREs in Huntington’s disease.
While more research is needed to identify how this could be applied to other conditions, the team remains optimistic their findings could inform future research and care for DM1, ASD and other conditions.
Funding: This study was funded by the Azrieli Foundation, the National Institutes of Health ( NIH), Myotonic Dystrophy Foundation, Muscular Dystrophy Association, the UNVL startup fund, the University of Florida Centre for Autism and Neurodevelopment, the National Science Centre, Poland, SickKids Research Institute, Brain Canada, the Government of Ontario, the University of Toronto McLaughlin Centre, the Canadian Institutes of Health Research ( CIHR ), The Petroff Family Foundation, Tribute Communities, The Marigold Foundation and SickKids Foundation.
About this Autism and genetics research news
Author: Francesca Pak
Source: Hospital for Sick Children
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes ” by Ryan Yuen et al. Nature Neuroscience
Abstract
Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes
Genome-wide enrichment of gene-specific tandem repeat expansions has been linked to autism spectrum disorder.
One such mutation is the CTG tandem repeat expansion in the 3′ untranslated region of the DMPK gene, which is known to cause myotonic muscular dystrophy type 1.
Although there is a clear clinical association between autism and myotonic dystrophy, the molecular basis for this connection remains unknown.
Here, we report that sequestration of MBNL splicing factors by mutant DMPK RNAs with expanded CUG repeats alters the RNA splicing patterns of autism-risk genes during brain development, particularly a class of autism-relevant microexons.
We demonstrate that both DMPK-CTG expansion and Mbnl null mouse models recapitulate autism-relevant mis-splicing profiles, along with social behavioral deficits and altered responses to novelty.
These findings support our model that myotonic dystrophy-associated autism arises from developmental mis-splicing of autism-risk genes.
